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Neurodevelopmental disorder with hypotonia, microcephaly, and seizures(NEDHYMS)

MedGen UID:
1710110
Concept ID:
C5394312
Disease or Syndrome
Synonym: NEDHYMS
 
Gene (location): ADARB1 (21q22.3)
 
Monarch Initiative: MONDO:0030025
OMIM®: 618862

Definition

Neurodevelopmental disorder with hypotonia, microcephaly, and seizures (NEDHYMS) is an autosomal recessive disorder characterized by global developmental delay with axial hypotonia, inability to sit or walk, and severely impaired intellectual development with absent language. Most patients develop early-onset intractable seizures that prevent normal development. Additional features include feeding difficulties with poor overall growth and microcephaly. Some patients may have spastic quadriplegia, poor eye contact due to cortical blindness, variable dysmorphic features, and nonspecific abnormalities on brain imaging (summary by Tan et al., 2020). [from OMIM]

Clinical features

From HPO
Unilateral cryptorchidism
MedGen UID:
98467
Concept ID:
C0431664
Congenital Abnormality
Absence of a testis from the scrotum on one side owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Interictal epileptiform activity
MedGen UID:
869073
Concept ID:
C4023491
Finding
Epileptiform activity refers to distinctive EEG waves or complexes distinguished from background activity found in in a proportion of human subjects with epilepsy, but which can also be found in subjects without seizures. Interictal epileptiform activity refers to such activity that occurs in the absence of a clinical or subclinical seizure.
Temporal cortical atrophy
MedGen UID:
870489
Concept ID:
C4024936
Disease or Syndrome
Atrophy of the temporal cortex.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
Plagiocephaly
MedGen UID:
78562
Concept ID:
C0265529
Congenital Abnormality
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Prominent metopic ridge
MedGen UID:
387953
Concept ID:
C1857949
Finding
Vertical bony ridge positioned in the midline of the forehead.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Congenital laryngomalacia
MedGen UID:
120500
Concept ID:
C0264303
Anatomical Abnormality
Laryngomalacia is a congenital abnormality of the laryngeal cartilage in which the cartilage is floppy and prolapses over the larynx during inspiration.
Round face
MedGen UID:
116087
Concept ID:
C0239479
Finding
The facial appearance is more circular than usual as viewed from the front.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Oval face
MedGen UID:
336480
Concept ID:
C1849025
Finding
A face with a rounded and slightly elongated outline.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
High anterior hairline
MedGen UID:
477667
Concept ID:
C3276036
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD above the mean. Alternatively, an apparently increased distance between the hairline and the glabella.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Increased nuchal translucency
MedGen UID:
869253
Concept ID:
C4023676
Finding
Nuchal translucency is the sonographic appearance of subcutaneous accumulation of liquid in the back of the fetal neck in the first trimester of pregnancy (11-14 gestational weeks of pregnancy).
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Professional guidelines

PubMed

Shah R, Eklund EA, Radenkovic S, Sadek M, Shammas I, Verberkmoes S, Ng BG, Freeze HH, Edmondson AC, He M, Kozicz T, Altassan R, Morava E
Mol Genet Metab 2024 Jun;142(2):108472. Epub 2024 Apr 23 doi: 10.1016/j.ymgme.2024.108472. PMID: 38703411Free PMC Article
Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, Piard J
Eur J Hum Genet 2023 Sep;31(9):1023-1031. Epub 2023 Jun 21 doi: 10.1038/s41431-023-01410-z. PMID: 37344571Free PMC Article
Battaglia A, Filippi T, Carey JC
Am J Med Genet C Semin Med Genet 2008 Nov 15;148C(4):246-51. doi: 10.1002/ajmg.c.30187. PMID: 18932224

Recent clinical studies

Etiology

Shah R, Eklund EA, Radenkovic S, Sadek M, Shammas I, Verberkmoes S, Ng BG, Freeze HH, Edmondson AC, He M, Kozicz T, Altassan R, Morava E
Mol Genet Metab 2024 Jun;142(2):108472. Epub 2024 Apr 23 doi: 10.1016/j.ymgme.2024.108472. PMID: 38703411Free PMC Article
Amin S, Møller RS, Aledo-Serrano A, Arzimanoglou A, Bager P, Jóźwiak S, Kluger GJ, López-Cabeza S, Nabbout R, Partridge CA, Schubert-Bast S, Specchio N, Kälviäinen R
Epilepsia Open 2024 Jun;9(3):832-849. Epub 2024 Mar 7 doi: 10.1002/epi4.12914. PMID: 38450883Free PMC Article
Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, Piard J
Eur J Hum Genet 2023 Sep;31(9):1023-1031. Epub 2023 Jun 21 doi: 10.1038/s41431-023-01410-z. PMID: 37344571Free PMC Article
Ivanov I, Pacheva I, Yordanova R, Sotkova I, Galabova F, Gaberova K, Panova M, Gheneva I, Tsvetanova T, Noneva K, Dimitrova D, Markov S, Sapundzhiev N, Bichev S, Savov A
CNS Neurol Disord Drug Targets 2023;22(2):207-214. doi: 10.2174/1871527321666220221100704. PMID: 35189806
Bain JM, Cho MT, Telegrafi A, Wilson A, Brooks S, Botti C, Gowans G, Autullo LA, Krishnamurthy V, Willing MC, Toler TL, Ben-Zev B, Elpeleg O, Shen Y, Retterer K, Monaghan KG, Chung WK
Am J Hum Genet 2016 Sep 1;99(3):728-734. Epub 2016 Aug 18 doi: 10.1016/j.ajhg.2016.06.028. PMID: 27545675Free PMC Article

Diagnosis

Greene D, Thys C, Berry IR, Jarvis J, Ortibus E, Mumford AD, Freson K, Turro E
Nat Med 2024 Aug;30(8):2165-2169. Epub 2024 May 31 doi: 10.1038/s41591-024-03085-5. PMID: 38821540Free PMC Article
Shah R, Eklund EA, Radenkovic S, Sadek M, Shammas I, Verberkmoes S, Ng BG, Freeze HH, Edmondson AC, He M, Kozicz T, Altassan R, Morava E
Mol Genet Metab 2024 Jun;142(2):108472. Epub 2024 Apr 23 doi: 10.1016/j.ymgme.2024.108472. PMID: 38703411Free PMC Article
Corona-Rivera JR, Martínez-Duncker I, Morava E, Ranatunga W, Salinas-Marin R, González-Jaimes AM, Castillo-Reyes KA, Peña-Padilla C, Bobadilla-Morales L, Corona-Rivera A, Orozco-Vela M, Brukman-Jiménez SA
Mol Genet Metab 2024 May;142(1):108469. Epub 2024 Mar 28 doi: 10.1016/j.ymgme.2024.108469. PMID: 38564972
Karaer K, Karaer D, Yüksel Z, Işikay S
Clin Dysmorphol 2022 Oct 1;31(4):167-173. Epub 2022 Jul 14 doi: 10.1097/MCD.0000000000000426. PMID: 36004946
Ji J, Shen L, Bootwalla M, Quindipan C, Tatarinova T, Maglinte DT, Buckley J, Raca G, Saitta SC, Biegel JA, Gai X
Cold Spring Harb Mol Case Stud 2019 Apr;5(2) Epub 2019 Apr 1 doi: 10.1101/mcs.a003756. PMID: 30755392Free PMC Article

Therapy

Su PH, Chen JY, Chen SJ, Yang KC
Pediatr Neonatol 2008 Jun;49(3):88-93. doi: 10.1016/S1875-9572(08)60019-4. PMID: 18947005
Overweg-Plandsoen WC, Groener JE, Wang D, Onkenhout W, Brouwer OF, Bakker HD, De Vivo DC
J Inherit Metab Dis 2003;26(6):559-63. doi: 10.1023/a:1025999914822. PMID: 14605501
Fattal-Valevski A, Bassan H, Korman SH, Lerman-Sagie T, Gutman A, Harel S
J Child Neurol 2000 Aug;15(8):539-43. doi: 10.1177/088307380001500808. PMID: 10961793
Tsay CH, Partridge JC, Villarreal SF, Good WV, Ferriero DM
J Child Neurol 1996 Jan;11(1):25-30. doi: 10.1177/088307389601100106. PMID: 8745381
Hall CA
Am J Hematol 1990 Jun;34(2):121-7. doi: 10.1002/ajh.2830340208. PMID: 1692663

Prognosis

Garrity M, Kavus H, Rojas-Vasquez M, Valenzuela I, Larson A, Reed S, Bellus G, Mignot C, Munnich A, Isidor B, Chung WK
Cold Spring Harb Mol Case Stud 2021 Aug;7(4) Epub 2021 Aug 2 doi: 10.1101/mcs.a006092. PMID: 34021018Free PMC Article
Gorman KM, Meyer E, Grozeva D, Spinelli E, McTague A, Sanchis-Juan A, Carss KJ, Bryant E, Reich A, Schneider AL, Pressler RM, Simpson MA, Debelle GD, Wassmer E, Morton J, Sieciechowicz D, Jan-Kamsteeg E, Paciorkowski AR, King MD, Cross JH, Poduri A, Mefford HC, Scheffer IE, Haack TB, McCullagh G; Deciphering Developmental Disorders Study; UK10K Consortium; NIHR BioResource, Millichap JJ, Carvill GL, Clayton-Smith J, Maher ER, Raymond FL, Kurian MA
Am J Hum Genet 2019 May 2;104(5):948-956. Epub 2019 Apr 11 doi: 10.1016/j.ajhg.2019.03.005. PMID: 30982612Free PMC Article
Santiago-Sim T, Burrage LC, Ebstein F, Tokita MJ, Miller M, Bi W, Braxton AA, Rosenfeld JA, Shahrour M, Lehmann A, Cogné B, Küry S, Besnard T, Isidor B, Bézieau S, Hazart I, Nagakura H, Immken LL, Littlejohn RO, Roeder E; EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan, Kara B, Hardies K, Weckhuysen S, May P, Lemke JR, Elpeleg O, Abu-Libdeh B, James KN, Silhavy JL, Issa MY, Zaki MS, Gleeson JG, Seavitt JR, Dickinson ME, Ljungberg MC, Wells S, Johnson SJ, Teboul L, Eng CM, Yang Y, Kloetzel PM, Heaney JD, Walkiewicz MA
Am J Hum Genet 2017 Apr 6;100(4):676-688. Epub 2017 Mar 23 doi: 10.1016/j.ajhg.2017.03.001. PMID: 28343629Free PMC Article
Bain JM, Cho MT, Telegrafi A, Wilson A, Brooks S, Botti C, Gowans G, Autullo LA, Krishnamurthy V, Willing MC, Toler TL, Ben-Zev B, Elpeleg O, Shen Y, Retterer K, Monaghan KG, Chung WK
Am J Hum Genet 2016 Sep 1;99(3):728-734. Epub 2016 Aug 18 doi: 10.1016/j.ajhg.2016.06.028. PMID: 27545675Free PMC Article
Tanaka AJ, Cho MT, Millan F, Juusola J, Retterer K, Joshi C, Niyazov D, Garnica A, Gratz E, Deardorff M, Wilkins A, Ortiz-Gonzalez X, Mathews K, Panzer K, Brilstra E, van Gassen KL, Volker-Touw CM, van Binsbergen E, Sobreira N, Hamosh A, McKnight D, Monaghan KG, Chung WK
Am J Hum Genet 2015 Sep 3;97(3):457-64. Epub 2015 Aug 20 doi: 10.1016/j.ajhg.2015.07.014. PMID: 26299366Free PMC Article

Clinical prediction guides

Maroofian R, Zamani M, Kaiyrzhanov R, Liebmann L, Karimiani EG, Vona B, Huebner AK, Calame DG, Misra VK, Sadeghian S, Azizimalamiri R, Mohammadi MH, Zeighami J, Heydaran S, Toosi MB, Akhondian J, Babaei M, Hashemi N, Schnur RE, Suri M, Setzke J, Wagner M, Brunet T, Grochowski CM, Emrick L, Chung WK, Hellmich UA, Schmidts M, Lupski JR, Galehdari H, Severino M, Houlden H, Hübner CA
Genet Med 2024 Mar;26(3):101034. Epub 2023 Dec 3 doi: 10.1016/j.gim.2023.101034. PMID: 38054405Free PMC Article
Giacomini T, Cordani R, Bagnasco I, Vercellino F, Giordano L, Milito G, Ferrero GB, Mandrile G, Scala M, Meli M, Falsaperla R, Luria G, De Grandis E, Canale E, Amadori E, Striano P, Nobili L, Siri L
Neuropediatrics 2023 Dec;54(6):433-438. Epub 2023 Oct 6 doi: 10.1055/s-0043-1775977. PMID: 37802085
Li J, Yuan Y, Liu C, Xu Y, Xiao N, Long H, Luo Z, Meng S, Wang H, Xiao B, Mao X, Long L
Hum Mutat 2022 Jul;43(7):940-949. Epub 2022 Apr 28 doi: 10.1002/humu.24386. PMID: 35438214
Garrity M, Kavus H, Rojas-Vasquez M, Valenzuela I, Larson A, Reed S, Bellus G, Mignot C, Munnich A, Isidor B, Chung WK
Cold Spring Harb Mol Case Stud 2021 Aug;7(4) Epub 2021 Aug 2 doi: 10.1101/mcs.a006092. PMID: 34021018Free PMC Article
Gorman KM, Meyer E, Grozeva D, Spinelli E, McTague A, Sanchis-Juan A, Carss KJ, Bryant E, Reich A, Schneider AL, Pressler RM, Simpson MA, Debelle GD, Wassmer E, Morton J, Sieciechowicz D, Jan-Kamsteeg E, Paciorkowski AR, King MD, Cross JH, Poduri A, Mefford HC, Scheffer IE, Haack TB, McCullagh G; Deciphering Developmental Disorders Study; UK10K Consortium; NIHR BioResource, Millichap JJ, Carvill GL, Clayton-Smith J, Maher ER, Raymond FL, Kurian MA
Am J Hum Genet 2019 May 2;104(5):948-956. Epub 2019 Apr 11 doi: 10.1016/j.ajhg.2019.03.005. PMID: 30982612Free PMC Article

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